More than 30 million Americans suffer from unrelieved chronic pain, such as nerve injury-induced neuropathic pain. Although a considerable amount is known about how chronic pain is induced, little is known about how acute pain naturally resolves. We hypothesize that disruption of local active pro-resolving processing will result in chronic pain. Current management of chronic pain mainly focuses on two types of drugs, ones that treat pain symptoms by blocking neurotransmission and those that modify disease progression by suppressing neuroinflammation. We now propose a novel approach for chronic pain therapy, using newly uncovered endogenous pro-resolving mediators. This approach focuses on novel endogenous lipid mediators namely resolvins and protectins that bring damaged system back to homeostasis by enhancing the phagocytic activity and clearance of local macrophages. Our recent results show that resolvins and protectins are very potent pro-resolving and anti-inflammatory agonists. Work in progress demonstrates that these novel endogenous mediators are also very effective, in nanogram dose range, in producing anti- hyperalgesic effects in animal models of inflammatory pain and neuropathic pain. We hypothesize that diminished production of resolvins and protectins after nerve injury will lead to the development of chronic pain. The overall goal of this application is to investigate whether and how resolvins and protectins can prevent and reverse neuropathic pain after nerve injury. We will employ multidisciplinary approaches, such as newly developed lipid mediator-lipidomics-informatics, animal behavior, electrophysiology, and several new biochemical systems including in vivo and in vitro assessment of macrophage phagocytosis to define the anti- hyperalgesic, pro-resolving, and anti-inflammatory roles of resolvins and protectins in animal models of neuropathic pain. These studies will involve formation of innovative partnership between Dr. Ji's pain research laboratory and Dr. Serhan's inflammation research group in the same department. In view of the results from work in progress, the results from the proposed studies will be transformative and have considerable impact on the entire pain community, from acute postoperative pain to chronic inflammatory pain and neuropathic pain.